Asthma is a major public health problem affecting over 23 million people in the US, resulting in excess of $50 billion in healthcare expenditures per year. There is increasing evidence suggesting that in utero exposures can influence the genome resulting in increased susceptibility to asthma. In utero smoke (IUS) exposure has been associated with asthma susceptibility; however, the biologic mechanisms underlying this association have not been fully elucidated. MicroRNAs (miRNAs) are known to fine-tune the relative expression of hundreds of target genes and provide stability to gene expression regulatory networks. Animal models demonstrate that miRNAs are integral to normal in utero development, and that abnormal miRNA expression during development results in postnatal disease, suggesting that miRNAs that are modified during development by IUS exposure may be critical determinants of asthma susceptibility later in life. However, the role of miRNAs has neither been investigated in the context of IUS exposure in human lung development, nor in the developmental origin of asthma. We propose a novel integrative genomics approach incorporating miRNAs, gene expression, and DNA methylation in human subjects to investigate the role of miRNAs and their integrative networks (INs) in lung development and asthma susceptibility. Our proposal describes our plan to: identify miRNAs and the INs that are expressed, and modified by IUS exposure in developing human lung, and are also associated with asthma susceptibility and disease severity. In addition to vastly expanding our knowledge of the role miRNAs and their INs in human lung development and the signature of IUS exposure, this project will aid in the identification of pathways for novel therapeutic agents for the treatment of asthma.

Public Health Relevance

This project seeks to identify microRNAs that are associated with in utero smoke (IUS) exposure in the human lung that may be a biomarker for asthma susceptibility later in life. Identification of an integrative network of IUS exposure during human lung development, which includes genomic and epigenetic data, may identify microRNAs and pathways for novel therapies and targeted preventive strategies for asthma. Since asthma remains a leading cause of childhood hospitalizations, school absences, and missed days of work in the United States, both novel therapies and preventive strategies have the potential to substantially decrease the morbidity and financial burden related to asthma worldwide.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL125734-04
Application #
9658546
Study Section
Infectious Diseases, Reproductive Health, Asthma and Pulmonary Conditions Study Section (IRAP)
Program Officer
Lachowicz-Scroggins, Marrah Elizabeth
Project Start
2016-04-01
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
Kho, Alvin T; McGeachie, Michael J; Moore, Kip G et al. (2018) Circulating microRNAs and prediction of asthma exacerbation in childhood asthma. Respir Res 19:128
Li, Xuan; Fu, Yuejiao; Wang, Xiaogang et al. (2018) Detecting Differentially Variable MicroRNAs via Model-Based Clustering. Int J Genomics 2018:6591634
Sharma, Sunita (2017) The Epigenetics of Intrauterine Smoke Exposure: Can Maternal Vitamin C Supplementation Prevent Neonatal Respiratory Disease? Am J Respir Crit Care Med 196:672-674